Fatigue In Multiple Sclerosis

Recent advances in the understanding of the pathophysiology of multiple sclerosis (MS) are providing fertile ground for the development of unique treatment approaches. Unfortunately, an air of pessimism remains pervasive in a large segment of MS patients as well as clinicians dealing with this entity. Indeed, the historical descriptions of this disease have been filled with bleak commentary. As Godfried Sonderdank, Court Physician of Schiedam, Holland, reported in the 14th century when describing a disease now thought to represent MS with slowly evolving weakness of three extremities, dysphagia, a variety of sensory disturbances, as well as bilateral visual symptomatology: "Believe me, there is no cure for this illness. It comes directly from God. Even Hippocrates and Gallenus would not be of any help here."( 1)

Generalized fatigue seems to be one of the most common complaints of patients with multiple sclerosis. Yet the importance of fatigue in terms of compromising the quality of life in MS patients may not be fully appreciated by healthcare practitioners. When recognized, treatment options are generally few and only minimally effective.

In a recent survey of neurologists it was found that most favored research directed toward understanding the cause of fatigue in multiple sclerosis, while one-third said research should be focused on the development of new medications.( 2) Medicines most commonly used to treat fatigue in multiple sclerosis include Pemoline and Amantadine.

A recent study demonstrated that in 46 MS patients with disabling fatigue, Pemoline was preferred in 51.2% compared to 46.3% who preferred placebo. Detracting side effects of Pemoline in this study included insomnia, anorexia, headache, irritability, dizziness, and nausea.( 3) Other investigators have reported a 31% benefit in the treatment of MS-associated fatigue using Amantadine.( 4) Side effects noted with Amantadine have included nausea, dizziness, light-headedness, insomnia, depression, irritability, hallucinations, and confusion.

With the destruction of myelin in MS, nerve conduction in the demyelinated fibers is slowed, becomes temperature sensitive, and then fatigues rapidly. Myelin, however, may regenerate, but the regenerated myelin is usually ineffective with respect to function.

Recently, Dutch investigators have studied the use of 4-aminopyridine ( 4-AP) in an attempt to improve multiple sclerosis symptoms.( 5) 4-AP is a potassium blocking chemical which has been demonstrated to increase nerve conduction through areas of demyelinization. The study evaluated 70 patients with clinically definite MS ranging in age from 23 to 68 years.

Subjects were evaluated using a standardized disability scale (Kurtzke) at 2, 6, 12, 14, 18, and 24 weeks with monitoring of blood levels of 4-AP. The most significant side effect was a one percent incidence of epileptic seizures. The study group clearly demonstrated improvements when compared to the placebo group with respect to various motor skills including ambulatory function.

The main emphasis until now with respect to developing treatment strategies for multiple sclerosis have been either anti-inflammatory or immunosuppressive, designed to limit the extent of an acute attack or prevent exacerbations and progression of the disease, respectively. 4-Aminopyridine, however, approaches MS treatment in a different light, attempting to reestablish function through demyelinative nerve pathways whose function is compromised. 4-AP is inexpensive, available, and thus far seems to demonstrate only minimal side effects. Finally, since fatigue in MS has been thought by some investigators to represent a consequence of defective nerve transmission, the use of 4-AP in this scenario seems quite rational.

Autoimmune Disease and Candida

The possible link between various autoimmune diseases and infection with the yeast Candida albicans has been described by well-respected researchers over the past two decades. As Trowbridge recently stated when discussing autoimmune diseases, "They appear to be among the growing number of otherwise unrelated disorders partially caused by inflammation and destruction of cells, tissues, and organs by the body's own antibodies (autoantibodies). These disorders belong to the autoimmune classification of diseases.

"Science has not explained why the body should lose the ability to distinguish between substances that are "self" and those that are "nonself.

"An accumulating stack of evidence is pointing the finger of suspicion directly at Candida albicans as well as at other parasites or infections. How the yeast organism fosters a compromise of normal immune function is the subject of investigation and much speculation by the worldwide scientific and clinical communities."( 6)

Because of the frequent association of candidiasis with generalized fatigue and the autoimmune nature of multiple sclerosis, we evaluated ten adult MS patient for the presence of Candida immune complexes and Candida antibodies. The diagnosis of MS was confirmed by history, physical examination, and magnetic resonance brain scanning in these patients. Quantitative serum levels of Candida IgG, IgA, IgM, and immune complexes were assayed using an enzyme-linked immunoassay. (Antibody Assay Laboratories, Santa Ana, California). Candida immune complexes contain IgG Candida antibodies, Candida antigen, and fragments of complement. Immune complexes are present in direct proportion to the Candida load. Candida immune complexes are perhaps the most sensitive test for active Candida-related illness.

Candida antibodies (IgM) are transiently elevated in acute infections. IgA antibodies are elevated in surface infections such as the mucosa of the mouth, gastrointestinal tract, and vagina or urethra. IgG antibodies are present in most adults and may persist long after the infection has been cured; therefore, elevated levels may simply indicate past infection.

Table 1 summarizes our findings. These data indicate elevated levels of Candida immune complexes in half of the subjects studied. In addition, Candida antibodies were frequently elevated as well with elevated levels of IgG seen in 40%, IgA in 40%, and IgM in 30%.

Because of the high frequency of gut dysbiosis (a state of disordered bowel flora ecology) in various autoimmune diseases as well as chronic fatigue immune deficiency syndrome (CFIDS), we performed stool analysis on nine adult patients with MS diagnosed by history, physical examination, and magnetic resonance brain scanning. We utilized a Comprehensive Digestive Stool Analysis (Great Smokies Diagnostic Laboratory, Asheville, North Carolina). This study provides a variety of useful data including digestive markers (digestion and absorption), metabolic markers (balance of a variety of short chain fatty acids), bacteriology including normal flora, imbalanced flora, and possible pathogens, ratio of gram positive to gram negative organisms, mycology evaluation including normal organisms and possible pathogens, macroscopic evaluation, as well as a dysbiosis index. In this study we were most interested in mycology, lactobacillus count, and dysbiosis index.

The results are summarized in Table 2. This study reveals the presence of Candida albicans in the stool specimens of one-third of the patients studied. The dysbiosis index was elevated in all patients and the lactobacillus count was depressed in all patients as well.

The relationship between Candida activity and chronic fatigue has certainly been well-described by various authors. We believe that these data provide compelling evidence that candidiasis may, at the very least, be a frequent occurrence in patients with multiple sclerosis.

In addition, these data seem to indicate that intestinal dysbiosis may be common in MS patients. Dysbiosis is certainly well-recognized in patients suffering from inflammatory bowel disease (also an autoimmune phenomenon), and it is certainly well-known that inflammatory bowel disease is often associated with extra-intestinal inflammatory manifestation such as arthritis, iritis/uveitis, and others. We believe, and these data suggest, that there is a strong likelihood that a relationship may exist between intestinal dysbiosis and multiple sclerosis. In a recent report in The Lancet,( 7) the frequency of white-matter lesions in 72 consecutive patients with inflammatory bowel disease, 48 with Crohn's disease, and 24 with ulcerative colitis was investigated. Magnetic resonance imaging studies of the brain were performed on the study group and compared to an age-matched healthy control population. This study found hyperintense focal white-matter lesions ranging from 2-8 mm. in diameter in 20 of 48 patients with Crohn's disease (42%), in 11 of 24 patients with ulcerative colitis (46%), and in 8 of 50 healthy volunteers (16%).

Interestingly, the authors' report: "The frequency of focal white-matter lesions in patients with inflammatory bowel disease was almost as high as that in patients with multiple sclerosis (65%).

We now routinely perform serum analysis for Candida immune complexes and Candida antibodies (IgG, IgM, and IgA) as well as a Comprehensive Stool Digestive Analysis on our multiple sclerosis patients.

MS patients with findings indicative of active candidiasis are generally treated with an antifungal agent, typically fluconazole (Diflucan), in dosages ranging from 100 mg. every other day to 150 mg. per day depending on patient size and disease activity. Typically, fluconazole is continued for flour to six weeks or even longer depending on response. Midway through treatment we typically assess liver transaminase function. We utilize a low carbohydrate diet as popularized by Dr. William Crook.( 8)

Patients demonstrating an elevated dysbiosis index with deficiencies of lactobacillus are generally treated initially utilizing Ultra-Flora Plus (fructo-oligosaccharides, concentrate of globulin protein from whey, Lactobacillus acidophilus, NCFM, Bifido bacterium infantis (A), one-half teaspoon twice a day on an empty stomach with distilled water, increased to one full teaspoon three times a day after one week. In more severe cases, we typically utilize a two to three week program of Ultra-Clear Sustain (Ref. A) which is a nutritional support program designed for patients suffering from dysbiosis. This program is utilized along with a diet eliminating caffeine, alcohol, wheat, and dairy products.'

In addition, it is critically important to recognize the importance of vitamin B-12 metabolism in the pathogenesis of multiple sclerosis as we described in a previous edition of TLfD (April 1993, pp. 304-305). Although we typically continue to assess vitamin B-12 levels, we have been more impressed of late with the usefulness of urine methylmalonic acid in providing more relevant information as to B-12 status.

We generally supplement our multiple sclerosis patients with high dosage vitamin B-12 given by IM injection. Typically, we will begin treatment with 1,000 mcg. of vitamin B-12 administered IM on a daily basis for a two-week period of time followed by a weekly injection for the following four to six weeks and then continue with 1,000 mcg. IM on a monthly basis. We are frequently able to instruct our patients in self-administration of B-12, thus minimizing inconvenience and cost.

This report demonstrates a significantly increased incidence of elevated Candida-related markers in patients with multiple sclerosis. Our success in reducing fatigue in multiple sclerosis with treatments designed specifically to reduce Candida activity lends further support for the suggested relationship between MS related fatigue and Candida activity.

Further, we suggest that intestinal dysbiosis may play a pivotal role with respect to the actual pathogenesis of multiple sclerosis as an autoimmune disease entity.

Correspondence:

David Perlmutter, M.D.

800 Goodlette Road North, Suite 270

Naples, Florida 33940 USA

941-649-7400 / Fax 941-649-6370

References
(1.) Medaer, R.: Does the History of Multiple Sclerosis Go Back As Far as the Fourteenth Century? Acta, Neurol. Scand., 60: 189-192, 1979.